Paroxysmal hypnogenic dyskinesia is associated with mutations in the PRRT2 gene

Abstract

Objective:To explore the potential causative genes of paroxysmal hypnogenic dyskinesia (PHD), which was initially considered a subtype of paroxysmal dyskinesia and has been recently considered a form of nocturnal frontal lobe epilepsy (NFLE).Methods:Eleven patients with PHD were recruited. Mutations in proline-rich region transmembrane protein-2 (PRRT2), myofibrillogenesis regulator 1 (MR-1), solute carrier family 2, member 1 (SLC2A1), calcium-activated potassium channel alpha subunit (KCNMA1), cholinergic receptor, nicotinic, alpha 4 (CHRNA4), cholinergic receptor, nicotinic, beta 2 (CHRNB2), cholinergic receptor, nicotinic, alpha 2 (CHRNA2), and potassium channel subfamily T member 1 (KCNT1) were screened by direct sequencing.Results:Two PRRT2 mutations were identified in patients with typical PHD. A mutation of c.649dupC (p.Arg217ProfsX8) was identified in a patient with PHD and his father who was diagnosed with paroxysmal kinesigenic dyskinesia. An additional mutation of c.640G>C (p.Ala214Pro) was identified in a sporadic patient and his asymptomatic mother. No mutations were found in the other screened genes.Conclusions:The present study identified PRRT2 mutations in PHD, extending the phenotypic spectrum of PRRT2 and supporting the classification of PHD as a subtype of paroxysmal dyskinesia but not NFLE. Based on the results of this study, screening for the PRRT2 mutation is recommended in patients with PHD.

Thalamocortical dysconnectivity in paroxysmal kinesigenic dyskinesia: Combining functional magnetic resonance imaging and diffusion tensor imaging

“…The PRRT2 is a causative gene of PKD . PRRT2 messenger RNA is thought to be predominantly expressed in neurons in the cortex and the basal ganglia, which are involved in the pathology of PKD patients.…”

“…The PRRT2 is a causative gene of PKD. 23,49 PRRT2 messenger RNA is thought to be predominantly expressed in neurons in the cortex and the basal ganglia, 50 which are involved in the pathology of PKD patients. As a consequence of increased glutamate release and subsequent neuronal hyperexcitability, 51 PRRT2 mutations can affect glutamate signaling and glutamate receptor activity through interaction with SNAP-25.…”

Paroxysmal motor disorders: expanding phenotypes lead to coalescing genotypes

“…Like KCNA1 , other genes may be associated with varied and ever expanding phenotypes or presentation may lack the namesake feature and may overlap multiple other genetically defined paroxysmal movement disorders. For example mutation in PRRT2 , classically associated with paroxysmal kinesigenic dyskinesia (PKD) may also present as nonkinesigenic dyskinesia, exercise‐induced dyskinesia, nocturnal dyskinesia, seizure or with hemiplegic spells . Conversely, across the broad category of paroxysmal movement disorders multiple genes may converge on similar phenotypes.…”

Unravelling of the paroxysmal dyskinesias

“…Interestingly, PRRT2 mutations have been recently identified in 2 out of 11 patients (18.2%) with PHD,20 which supports the inclusion of PHD among the PxD. Moreover, PRRT2 mutations have been further associated with a phenotype reminiscent of benign paroxysmal torticollis of infancy (BPTI)21 and, in the case of biallelic mutations, with a complex phenotype including neurodevelopmental delay 22.…”